Biology and pathophysiology of nervous system metastases
INTRODUCTION Molecular biological investigations over the past 25 years have confirmed that the transformed phenotype of solid tumor cells is highly complex and results from the dysfunction of a variety of interrelated regulatory pathways (1-7). The transformation process involves amplification or overexpression of oncogenes in combination with loss or lack of expression of tumor suppressor genes. Oncogenes that have been demonstrated to be important for tumorigenesis include platelet-derived growth factor and its receptor (PDGF and PDGFR), epidermal growth factor and its receptor (EGF and EGFR), fibroblast growth factor (FGF), insulin-like growth factor (IGF), CDK4, mdm-2, ras, gli, Akt, and mTOR. Many of these oncogenes are involved in membrane mediated and internal signal transduction pathways that affect cell proliferation and growth potential. Tumor suppressor genes of importance in the transformation process include p53, Rb, p16, and p15 (i.e., INK4a and INK4b), and PTEN. In addition, tumor suppressor genes are also suspected to reside on many chromosomes, including 22q, 1p, 19q, 11p, and 10q, since these regions frequently demonstrate loss of heterozygosity in cytogenetic studies. Most of these tumor suppressor genes function as negative regulators of the cell cycle, while others are inhibitors of important internal signal transduction pathways. Other avenues of research have demonstrated the importance of microRNA and epigenetic mechanisms of gene regulation in neoplastic transformation. MicroRNAs are small nucleotide RNA molecules with the ability to alter gene transcription, and can function as oncogenes or tumor suppressor genes (8,9). Epigenetic mechanisms, which include processes such as DNA methylation, histone modification, and alteration of chromatin compartments, are novel mechanisms for controlling gene transcription that have also been implicated in malignant transformation (10,11). This chapter reviews the major pathways involved in malignant transformation, with a focus on solid tumors, as well as the molecular mechanisms underlying the process of cancer metastasis.